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Two bipyridine isomers (2,2′- and 4,4′-), used as coformers and ligands in coordination chemistry, were subjected to solid form screening and crystal structure prediction. One anhydrate and a formic acid disolvate were crystallized for 2,2′-bipyridine, whereas multiple solid-state forms, anhydrate, dihydrate, and eight solvates with carboxylic acids, including a polymorphic acetic acid disolvate, were found for the 4,4′-isomer. Seven of the solvates are reported for the first time, and structural information is provided for six of the new solvates. All twelve solid-state forms were investigated comprehensively using experimental [thermal analysis, isothermal calorimetry, X-ray diffraction, gravimetric moisture (de)sorption, and IR spectroscopy] and computational approaches. Lattice and interaction energy calculations confirmed the thermodynamic driving force for disolvate formation, mediated by the absence of H-bond donor groups of the host molecules. The exposed location of the N atoms in 4,4′-bipyridine facilitates the accommodation of bigger carboxylic acids and leads to higher conformational flexibility compared to 2,2′-bipyridine. For the 4,4′-bipyridine anhydrate ↔ hydrate interconversion hardly any hysteresis and a fast transformation kinetics are observed, with the critical relative humidity being at 35% at room temperature. The computed anhydrate crystal energy landscapes have the 2,2′-bipyridine as the lowest energy structure and the 4,4′-bipyridine among the low-energy structures and suggest a different crystallization behavior of the two compounds., The solid form landscapes of 2,2′- and 4,4′-bipyridine were explored experimentally and computationally. The position of the nitrogen atoms defines not only the conformational flexibility of the molecule but also the crystallization behavior. 4.4′-Bipyridine was found to be more prone to solvate (including hydrate) formation than its 2,2′-isomer.

Commercial samples of strychnine sulfate were used as the starting material in crystallization experiments accompanied by stability studies. Eight hydrate forms (HyA–HyG), including five novel hydrates, were verified. The crystal structures of HyA (“pentahydrate”) and HyF (“hexahydrate”) were determined from single-crystal X-ray diffraction data. HyF was identified as the most stable hydrate at high water activities at room temperature (RT), and HyA and HyC were also found to be stable at ambient conditions. Long-time storage experiments over nearly two decades confirm that these three hydrates are stable at ambient conditions (20–60% relative humidity). The other five hydrates, HyB (“dihydrate”), HyD, HyE, HyG, and HyH, are only observable at the low(est) relative humidity (RH) levels at RT. Some of these latter forms can only exist within a very narrow RH range and are therefore intermediate phases. By applying a range of complementary experimental techniques such as gravimetric moisture sorption analysis, thermal analysis, moisture controlled PXRD measurements, and variable temperature IR spectroscopy in combination with principal component analysis, it was possible to identify the distinct hydrate phases and elucidate their stability and dehydration pathways. The observed (de)hydration routes, HyA ↔ HyB, HyC ↔ HyD ↔ HyE, HyF ↔ HyG ↔ HyH and HyF → HyA ↔ HyB, depended on the initial hydrate form, particle size, and atmospheric conditions. In addition, a transformation from HyC/HyA to HyF occurs at high RH values at RT. The specific moisture and temperature conditions of none of the applied drying regimes yielded a crystalline water-free form, which highlights the essential role of water molecules for the formation and stability of the crystalline strychnine sulfate phases., The complex moisture- and temperature-dependent interconversion pathways and the stability of eight hydrate forms of strychnine sulfate were unraveled by a complementary approach comprising gravimetric moisture (de)sorption analysis, moisture controlled powder X-ray diffraction measurements, thermal analysis, and variable temperature infrared spectroscopy combined with multivariate data treatment. The study highlights the importance of high-resolution, moisture-dependent investigations for gaining insight into the structural reorganization and transient states of hydrates.

A method for structure solution in thin films that combines grazing incidence X-ray diffraction data analysis and crystal structure prediction was presented in a recent work (Braun et al. Cryst. Growth Des.2019, DOI: 10.1021/acs.cgd.9b00857). Applied to phenytoin form II, which is only detected in films, the approach gave a very reasonable, but not fully confirmed, candidate structure with Z = 4 and Z′ = 2. In the present work, we demonstrate how, by calculating and measuring the crystal Raman spectrum in the low wavenumber energy region with the aim of validating the candidate structure, this can be further refined. In fact, we find it to correspond to a saddle point of the energy landscape of the system, from which a minimum of lower symmetry may be reached. With the new structure, with Z = 4 and Z′ = 2, we finally obtain an excellent agreement between experimental and calculated Raman spectra., Experimental low wavenumber Raman spectroscopy validates the presence of a non-centrosymmetric packing arrangement that is energetically very close to a centrosymmetric saddle point structure.

Understanding the behavior and properties of molecules assembled in thin layers requires knowledge of their crystalline packing. The drug phenytoin (5,5-diphenylhydantoin) is one of the compounds that can be grown as a surface induced polymorph. By using grazing incidence X-ray diffraction, the monoclinic unit cell of the new form II can be determined, but, due to crystal size and the low amount of data, a full solution using conventional structure solving strategies fails. In this work, the full solution has been obtained by combining computational structure generation and experimental results. The comparison between the bulk and the new surface induced phase reveals significant packing differences of the hydrogen-bonding network, which might be the reason for the faster dissolution of form II with respect to form I. The results are very satisfactory, and the method might be adapted for other systems, where, due to the limited amount of experimental data, one must rely on additional approaches to gain access to more detailed information to understand the solid-state behavior., The change in molecular packing of phenytoin, when prepared in thin films, is evaluated by X-ray experiments and structure calculation, and the observed differences in the H-bonding network explain the recent results showing faster dissolution.

Elucidating the structure relationships and transformation pathways of the solid forms of gandotinib was an enormous challenge. Only seven of the eleven experimentally observed forms crystallized directly from solution: a neat form (I), a tetrahydrate (Hy4), a 3.0–3.7-hydrate (HyY), and four solvates (methanol, n-propanol, n-butanol, and N-methyl-2-pyrrolidone). The four remaining forms (II, Hy2.2, Hy1.3, and HyX) were produced by dehydration and/or rehydration processes. Interconversion of the anhydrates and hydrates of gandotinib with small changes in the relative humidity complicated identifying and characterizing the crystalline forms to such an extent that some experiments conducted in the humidity of summer could not be reproduced in the winter, and vice versa. Thus, with solid-state transformations being the only route to four of the solid forms, elucidating the crystal structural relationships underpinning the dehydration–rehydration pathways as a function of temperature and humidity required not ...

The reversible solid-state phase transformation between the neat forms II and III of dapsone (DDS) was studied using thermal analytical methods, variable temperature X-ray diffraction and solid-state modeling at the electronic level. The first order III ↔ II phase transformation occurs at 78 ± 4 °C with a heat of transition of 2 kJ mol–1 and a small hysteresis. The two isosymmetric polymorphs (both P212121) differ only in movement of layers of molecules and show a small variation in conformation. The combination of variable-temperature single-crystal structure determinations and pair-wise intermolecular energy calculations allowed us to unravel the single-to-single crystal transformation at a molecular level, to estimate the molecular contributions to the heat of transformation and to rationalize why the room and low temperature form III is the less dense polymorphic form, which is a rare phenomenon in enantiotropically related pairs of polymorphs in molecular crystals.

The solid form landscape of 5-HT2a antagonist 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid hydrochloride (B5HCl) proved difficult to establish. Many crystalline materials were produced by solid form screening, but few forms readily grew high quality crystals to afford a clear picture or understanding of the solid form landscape. Careful control of crystallization conditions, a range of experimental methods, computational modeling of solvate structures, and crystal structure prediction were required to see potential arrangements of the salt in its crystal forms. Structural diversity in the solid form landscape of B5HCl was apparent in the layer structures for the anhydrate polymorphs (Forms I and II), dihydrate and a family of solvates with alcohols. The alcohol solvates, which provided a distinct packing from the neat forms and the dihydrate, form layers with conserved hydrogen bonding between B5HCl and the solvent, as well as stacking of the aromatic rings. The ability of the alcohol hydrocarbon moieties to efficiently pack between the layers accounted for the difficulty in growing some solvate crystals and the inability of other solvates to crystallize altogether. Through a combination of experiment and computation, the crystallization problems, form stability, and desolvation pathways of B5HCl have been rationalized at a molecular level., Through a combination of experiment and computation, the crystallization problems, form stability, and desolvation pathways of 3-(4-(benzo[d]isoxazole-3-yl)piperazin-1-yl)-2,2-dimethylpropanoic acid hydrochloride (B5HCl) have been rationalized at a molecular level.

New polymorphs of thymine emerged in an experimental search for solid forms, which was guided by the computationally generated crystal energy landscape. Three of the four anhydrates (AH) are homeoenergetic (A° – C) and their packing modes differ only in the location of oxygen and hydrogen atoms. AHs A° and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Anhydrates AHs A° and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Analysis of the crystal energy landscape for alternative AH C hydrogen bonded ribbon motifs identified a number of different packing modes, whose 3D structures were calculated to deviate by less than 0.24 kJ mol–1 in lattice energy. These structures provide models for stacking faults. The three anhydrates A° – C show strong similarity in their powder X-ray diffraction, thermoanalytical and spectroscopic (IR and Raman) characteristics. The already known anhydrate AH A° was identified as the thermodynamically most stable form at ambient conditions; AH B and AH C are metastable but show high kinetic stability. The hydrate of thymine is stable only at water activities (aw) > 0.95 at temperatures ≤ 25 °C. It was found to be a stoichiometric hydrate despite being a channel hydrate with an unusual water:thymine ratio of 0.8:1. Depending on the dehydration conditions, either AH C or AH D is obtained. The hydrate is the only known precursor to AH D. This study highlights the value and complementarity of simultaneous explorations of computationally and experimentally generated solid form landscapes of a small molecule anhydrate ↔ hydrate system.

Hydrate and anhydrate crystal structure prediction (CSP) of creatine (CTN), a heavily used, poorly water-soluble, zwitterionic compound, has enabled the finding and characterization of its anhydrate polymorphs, including the thermodynamic room temperature form. Crystal structures of the novel forms were determined by combining laboratory powder X-ray diffraction data and ab initio generated structures. The computational method not only revealed all experimental forms but also predicted the correct stability order, which was experimentally confirmed by measurements of the heat of hydration., A computationally driven experimental search for anhydrate and hydrate solid forms of creatine enabled the finding and characterization (structure and stability) of its three polymorphs and the monohydrate. The computational method not only found the experimental forms but also correctly predicted the stability order, which was experimentally confirmed by measurements of the heat of hydration.

We report the structure of the fifth monohydrate of gallic acid and two additional anhydrate polymorphs and evidence of at least 22 other solvates formed, many containing water and another solvent. This unprecedented number of monohydrate polymorphs and diversity of solid forms is consistent with the anhydrate and monohydrate crystal energy landscapes, showing both a wide range of packing motifs and also some structures differing only in proton positions. By aiding the solution of structures from powder X-ray diffraction data and guiding the screening, the computational studies help explain the complex polymorphism of gallic acid. This is industrially relevant, as the three anhydrates are stable at ambient conditions but hydration/dehydration behavior is very dependent on relative humidity and phase purity., An extensive experimental screen for solid forms, driven by computationally generated anhydrate and monohydrate crystal energy landscapes, revealed the fifth (!) monohydrate structure of gallic acid, structures of two additional anhydrate polymorphs, and evidence of at least 22 solvates. The application of computational studies in combination with other analytical techniques helps unravel the complex polymorphic system of gallic acid.

Following the computational prediction that (RS)-naproxen would be more stable than the therapeutically used and more studied homochiral (S)-naproxen, we performed an interdisciplinary study contrasting the two compounds. The crystal structure of the racemic compound was solved from powder X-ray diffraction data (Pbca) and showed no packing similarity with the homochiral structure (P21). The binary melting point phase diagram was constructed to confirm the nature of the racemic species, and differential scanning calorimetric and solubility measurements were used to estimate the enthalpy difference between the crystals (ΔHR+S→RScry) to be −1.5 ± 0.3 kJ·mol–1 at T ∼ 156 °C and −2.4 ± 1.0 kJ·mol–1 in the range 10–40 °C. A comparison of the different approximations involved in estimating ΔHR+S→RScry implied that the difference in the lattice energies overestimated the stability of the (RS) crystal. The naproxen lattice energy landscape confirmed that all the practically important crystal structures have been ...

A combined experimental and computational study was undertaken to establish the solid-state forms of β-resorcylic acid (2,4-dihydroxybenzoic acid). The experimental search resulted in nine crystalline forms: two concomitantly crystallizing polymorphs, five novel solvates (with acetic acid, dimethyl sulfoxide, 1,4-dioxane, and two with N,N-dimethyl formamide), in addition to the known hemihydrate and a new monohydrate. Form II°, the thermodynamically stable polymorph at room temperature, was found to be the dominant crystallization product. A new, enantiotropically related polymorph (form I) was obtained by desolvation of certain solvates, sublimation experiments, and via a thermally induced solid−solid transformation of form II° above 150 °C. To establish their structural features, interconversions, and relative stability, all solid-state forms were characterized with thermal, spectroscopic, X-ray crystallographic methods, and moisture-sorption analysis. The hemihydrate is very stable, while the five solvates and the monohydrate are rather unstable phases that occur as crystallization intermediates. Complementary computational work confirmed that the two experimentally observed β-resorcylic acid forms I and II° are the most probable polymorphs and supported the experimental evidence for form I being disordered in the p-OH proton position. These consistent outcomes suggest that the most practically important features of β-resorcylic acid crystallization under ambient conditions have been established; however, it appears impractical to guarantee that no additional metastable solid-state form could be found., An extensive experimental screen, coupled with a computational study, revealed seven new solid-state forms of β-resorcylic acid. The known, stable polymorph II° shows a reversible phase transformation to the new, kinetically stable, probably disordered high temperature form I. The study provides a consistent picture of the solid-state of β-resorcylic acid.

Three polymorphs of the calcimimetic cinacalcet hydrochloride were characterized by a variety of methods including thermal analysis (hot-stage microscopy and differential scanning calorimetry), vibrational spectroscopy (FT-IR and FT-Raman spectroscopy), and X-ray diffractometry (powder and single crystal). The crystal structures of all polymorphs have been determined either from single crystals (form III°) or from powder data (forms I and II). Forms III° and I both exhibit an orthorhombic cell with space group P212121, whereas form II crystallizes in the triclinic space group P1. All three polymorphs show basically the same hydrogen-bond synthon, and the structural differences are associated with conformational changes. In contrast to form III°, form II shows two conformationally different molecules, and in the high temperature form I the phenyl moiety is dynamically disordered. Among the three enantiotropically related polymorphs, form III° (Tfus: 165 °C) is the thermodynamically stable modification belo...

An intriguing example of conformational and color polymorphism is observed in p-tolyl-(2,4,6-trinitrophenyl)-amine (picryltoluidine, PT), which forms two crystalline modifications, the red form I R and the orange form II O . Solvated crystals with a PT/solvate ratio of 1:1 (pyridine) or 2:1 (benzene, chlorobenzene, toluene, or xylene) were obtained only from aromatic solvents, albeit with some difficulty, from aromatic solvents. The crystallization from all other tested solvents produced either a highly pure phase or a mixture of the two anhydrous forms. Single crystal structure determinations were carried out on the seven solid forms, along with a characterization by thermal analysis (hot stage microscopy, DSC, TGA), vibrational spectroscopy (IR, Raman) and X-ray powder diffraction. The PT molecules in all structures exhibit intramolecular N−H···O bonds. The different colors are attributed to intramolecular electronic effects due to an increased delocalization of the secondary amino nitrogen lone-pair el...